A new class of non-opioid pain-relieving drugs has recently been discovered that is chemically related to histamine. The prototype (named improgan) shows the following characteristics after direct injection into the rodent brain: a) highly effective, morphine-like antinociception on thermal and mechanical tests, b) no impairment of motor coordination or locomotor activity, c) a non-opioid mechanism that is independent of known receptors for histamine and 60 other targets, d) lack of tolerance with daily dosing, and e) unique structure-activity relationships among chemical congeners, suggesting the possible existence of a novel histamine receptor. However, little is known about the sites and mechanisms of action of improgan. To approach these issues, the following studies will be performed in rats. 1) Microinjection mapping studies will identify the CNS areas mediating improgan analgesia. Sites known to comprise the endogenous pain-relieving system will be studied (the periaqueductal grey, the rostral ventral medulla [including the nucleus raphe magnus] and the spinal cord). 2) The effects of these microinjections will be assessed on two measures of motor function (rotorod test and locomotor activity) to assess the specificity of improgan analgesia. 3) Microinjection studies with transmitter agonists and antagonists will identify the supraspinal and spinal transmitter mechanisms that mediate improgan analgesia. 4) Two kinds of experiments will search for the improgan receptor: a) the improgan-induced modulation of 35S-GTPgammaS binding in brain membranes will be studied, and b) homogenate and autoradiography techniques will study the binding of a radiolabeled derivative of improgan. These studies may also help to develop an in vitro assay for improgan-like activity. 5) To determine if improgan-like analgesics are effective in preclinical models of human inflammatory pain, the activity of improgan will be studied in the formalin nociceptive test in rats. The proposed experiments will characterize the fundamental neuronal mechanisms of non-opioid analgesia, and may lead to the discovery of a new histamine receptor, and/or to the development of new pharmacotherapies for acute and chronic pain.